Sonography guided embryo transfer for in vitro fertilization

ABSTRACT

The present provides novel systems and methods to facilitate embryo transfer, to maximize implantation rates and to improve pregnancy rates resulting from In Vitro fertilization.

This is a continuation of co-pending application Ser. No. 11/131,903,filed May 17, 2005, which claims the benefit of U.S. ProvisionalApplication No. 60/572,267, filed May 17, 2004, which is herebyincorporated by reference as if it was set forth herein in its entirety.

FIELD OF THE INVENTION

The current invention generally relates to systems and methods for invitro fertilization, and more specifically, to the use of ultrasound toimplant an embryo at an optimal location in the uterine cavity.

BACKGROUND OF THE INVENTION

The success rates in patients undergoing In Vitro Fertilization (IVF)has improved tremendously over the past few years. Better ovulationinduction protocols as well as great improvements in the IVF laboratoryhave greatly contributed to the increased pregnancy rate. One area thathas received more attention than usual is the embryo transfer technique.While many variations exist in the preparation of the cervix, the typeof transfer catheter used, the duration of the transfer and the use oftrial transfers, most physicians in the United States as well as othercountries are now performing embryo transfers under ultrasound guidance.Since the introduction of the ultrasound as an aid to embryo transfer,physicians have reported a greater ease of transfer, and more accurateplacement of the embryos within the uterine cavity. The patients alsoenjoy watching their embryos, distracting them from the actual transferprocedure.

Ultrasound guided embryo transfer has been around since 1985, however ithas become almost universal in the past three years. Since then,multiple studies have shown higher pregnancy rates when performingembryo transfers in conjunction with ultrasonography (1-4). Theadvantages of ultrasound guided embryo transfers include thefacilitation of embryo transfer as well as physician's ability tovisualize catheter and embryo placement.

Although 2D ultrasound guidance has been increasingly utilized,controversy exists regarding the ideal placement of the embryos withinthe uterine cavity. Various studies have been published in regards tothe ideal area of embryo transfer. However these studies only representgeneralized locations, not taking into consideration that uterineanatomy varies among women.

Integral to a successful in vitro fertilization (IVF) is the placementof the embryo in the uterine cavity. The transfer of an embryo from thelaboratory to the uterus is generally referred to as embryo transfer.Embryo transfer is generally the final step in an IVF cycle, and asuccessful embryo transfer is a prerequisite for achieving pregnancy.While the IVF technology and success rates have come a long way, therestill remains room for improvement. The pregnancy rate is highlyinfluenced by the quality of the embryos, the receptivity of theendometrium and by the transfer technique (5).

Because of the importance of the embryo transfer phase, efforts havebeen made since the introduction of IVF approximately twenty years agoto determine the “best spot” within the uterine cavity to implant theembryo. Two dimensional (2D) sonography has been used for some time toaid in embryo transfer. While this represented an advance overimplanting embryos without any guidance whatsoever, two dimensionalsonography has still only provided guidance as to the general area atwhich the embryo should be released for implantation. There is still noconsensus of what the ideal choice for implantation is for embryos. In astudy by Baba et al, embryos were transferred to the midfundal area in60 patients. Among the 22 pregnancies, 80% of the embryos implanted inthe areas to which they were transferred, while 20% implanted in otherareas (6).

Other studies have been published suggesting various locations withinthe uterine cavity where embryos should be released. These studies havesuggested implantation in locations ranging from the lower uterinesegment, to various distances (0.5 cm-2.0 cm) from the uterine fundus.However, these distances still only represent generalized locations.Furthermore, the value to place on these distances as guidelinesdecreases when considering that the configuration and dimensions of theuterine cavity vary between women. The location of embryo transfer inrespect to the uterine anatomy also varies among physicians. Somestudies have shown that the optimal location for embryo transfer is0.5-1 cm away from the uterine fundus (3), while some believe that thetip of the catheter should be 1.5 cm from the uterine fundus (2).However, others have shown that transfer should be in the lower tomiddle uterine segment (7). In a different study by Pope et al, it wasdemonstrated that for every additional millimeter the embryos are placedaway from the uterine fundus, the clinical pregnancy rate increases by11% (8). In a recent randomized study by Franco et al, embryos weredeposited in the lower or upper half of the endometrial cavity and therewas no difference in pregnancy or implantation rates (9).

In sum, two dimensional sonography does not provide the clinician withan optimal view of where the embryo should be released. Accordingly,there exists a need for a more accurate system with which to determinethe optimal location at which to implant an embryo. There also exists aneed for embryo transfer to be carried out with less trauma to the womanundergoing IVF.

SUMMARY OF THE INVENTION

An aspect of the invention is determining the optimal location at whichto implant an embryo. In the discussion below, this is referred to asthe Maximum Implant Potential point, or MIP point.

Another aspect of the invention is the use of three and four dimensionalultrasound to view the uterine cavity to determine the MIP point, and tohelp guide the clinician's catheter to the MIP point when implantingembryo(s).

Another aspect of the invention is the overall procedure involving theuse of an ultrasound machine to implant embryo(s) in an IVF cycle.

A further aspect of the invention is an integrated system for thedetermination of the most suitable implantation point so as to maximizefertilization rates in individual women.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-section of the female reproductive system. Thelocation of the MIP is as indicated.

FIG. 2 is a conventional 2D ultrasound image of a uterus

FIG. 3 is a cross-section of the uterine cavity.

FIG. 4 represents a split screen of an ultrasound machine showing twodimensional and three/four dimensional views of the uterine cavity.

FIG. 5 shows a 3D ultrasound image of the uterine cavity. The Maximalimplantation potential (MIP) point is marked with an asterisk.

FIG. 6 shows how an embryo flash is confirmed on 3D ultrasound aftertransfer in area of maximal implantation potential.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Since the recent introduction of 3 D ultrasound it is possible for thefirst time to visualize the uterine cavity as a whole (FIG. 5). 3Dsonography can improve visualization of the uterus in patients withnormal anatomy and especially in those with uterine anomalies, e.g.bicornuate uterus. Thus, the present invention provides a maximalimplantation potential (MIP) point as a target for embryo transfers. TheMIP point is defined below and is shown in FIGS. 1, 4 and 5.

The uterine cavity resembles an inverted triangle and the fallopiantubes open into the cavity, one in each of the upper regions of thetriangle. The MIP is the intersection of these two imaginary lines, oneoriginating in each fallopian tube, within the inverted triangle. Innatural pregnancies, fertilization usually occurs in the ampullarysegment of the fallopian tube and the pre-embryo then travels down tothe uterus and usually implants in the anterior or posterior segment ofthe uterus close to it trajectory line, where the endometrium is thethickest and has the greatest blood flow. In patients undergoing InVitro Fertilization, the fallopian tubes are bypassed, placing theembryos directly into the uterus. Therefore by using the MIP point,placement of the embryos occurs where nature intended.

Because of individual anatomical differences, the MIP point can beindividually tailored. Further advances in 3D Ultrasonography as well asthe introduction of the 4D Sonography make it possible to visualize thetransfer catheter in real time as it moves towards its target: the MIPpoint.

Thus, the current invention involves the determination of the MIP pointand the accurate release of embryos with the use of three and fourdimensional sonography. As seen with the current invention, the use ofthree and four dimensional sonography allows the clinician to view theintrauterine cavity in a noninvasive manner. It is preferred that theclinician undertaking the techniques described herein receive trainingin the use of three and four dimensional sonography machines and currentimaging modalities.

The technique of the current invention generally involves (a) expandingthe bladder an appropriate amount to shift the uterus from an anteflexedposition to lessen the angle between the cervix and the uterine cavity,(b) locating the “maximum implantation potential point” (MIP) with theaid of three dimensional sonography and (c) implanting the embryo in theuterus with the aid of four dimensional sonography. During thisprocedure, scanning is preferably transabdominal.

Before describing the procedure further, the MIP point is firstdiscussed with reference to the cross-sectional view of the uterinecavity of FIG. 1. As shown, the uterine cavity generally resembles atriangle, and the fallopian tubes open into the uterine cavity in eachone of the upper regions of the triangle. The fallopian tubes enter theuterine cavity at an angle of approximately 45 degrees on the left and135 degrees on the right.

In natural pregnancies, the embryo travels down the fallopian tube intothe uterine cavity. In connection with the current invention, it hasbeen observed that in the majority of pregnancies, the embryo implantsin the middle of the triangle in the anterior or posterior uterine wall.In that location, the endometrial lining is the thickest, which providesfor increased blood flow and consequently increased potential forsuccessful implantation. Accordingly, it is preferred to implant anembryo at that location.

The views provided by three and four dimensional sonography allow theclinician to determine where the MIP point is. More specifically, byextending lines depicting the axes of the fallopian tubes into theuterine cavity, it is seen that they intersect. Their intersectionrepresents the MIP point where potential for successful implantation isoptimal.

It bears note that prior to the current invention, such views of theuterine cavity were not possible with two-dimensional ultrasound, shownin FIG. 2. Accordingly, the MIP point and the accuracy associatedtherewith were not even available for embryo transfer procedures.

The procedure of the current invention is now described in more detail.In the vast majority of cases, the uterus is naturally in an anteflexedposition such that there is a sharp angle created between the cervix andthe uterine cavity. Referring to FIG. 3, in an anteflexed position, theangle of the uterus would be 90 degrees or more as opposed to the 30degree angle shown. This is problematic for the clinician since thecatheter used to deliver embryos is typically soft and cannot bemanipulated to engage curves.

Accordingly, it is preferred that the woman undergoing the embryotransfer drink an appropriate amount of water or other liquid to expandthe bladder to move the uterus from an anteflexed position. For example,the patient may drink 32 oz. or other quantity of water or other liquidone hour (or some other suitable time) prior to the scheduledappointment. The angle may be viewed using two dimensional sonography.As shown in FIG. 3, it is preferred that the angle reach approximately30 degrees for the procedure to occur.

Prior to embryo transfer, the sonography machine suited for use with thecurrent invention should be adjusted to appropriate settings.Adjustments are generally necessary since each patient's physicalattributes will differ. The adjustments may occur while the patient'sbladder is filling to the appropriate level.

In a preferred embodiment, a General Electric Voluson 730 sonographymachine may be used. This unit provides both three-dimensional imagesand four dimensional, i.e., moving, images. The following protocol maybe followed, but it should be noted that the following protocol is anexample only, and is not intended to limit the current invention.

1) Turn on sonography unit.

2) Probe/Program Selection. Press the probe key. On the probe selectionmenu, probe RAB 2-5 3D may be used.

3) Application: Obstetrics.

4) Settings: 1. Trimester. Press the Freeze/Run key.

5) Scan 2D to ascertain adequate distension of the urinary bladder anddesired position of the uterus.

6) Use the following settings on 2D before switching to 3D/4D.

Frequency resolution: Penet.

OTI: Adipose

7) Adjust Focal Point and depth. Focal point at the endometrial cavity.Enlarge image to include the full distance from the cervix to theuterine fundus.

8) Switching to 3D/4D, activate the Volume Mode (Hardkey).

9) Select 4D on the on the touch panel.

10) Display format: Select a ROI (left side of FIG. 4) with 4D image.

11) 3D/4D Setting: Touch Surface. 3D Orientation: 0 degrees.

12) Volume angle 25 degrees. Quality: High 2.

13) Position the Render Box to include the full length of the uterinecervix to endometrial cavity. Adjust size and content of the Render Box.

14) Start scanning. Reference image: In the ROI the uterine cavity willappear in a 15 degrees. Rotate the image slightly to become horizontalusing the “Y” axis rotary key.

15) Using the Trackball raise the image in the ROI display to the levelof the green line to overlap the Uterine canal and cavity.

16) On the 4D side the uterine canal and cavity will appear. DetermineMIP. This may be accomplished by visualizing the intersection point ofthe lines representing the axes of the fallopian tubes.

17) Adjust thresholds, contrast and other color adjustments to obtainthe best image.

It should be noted that the use of moving images provided by 4D ispreferred. However, those portions of the protocols described hereininvolving 4D could be achieved using 3D.

The procedure associated with the actual embryo transfer is now morefully described. As a speculum is placed in the vagina by the performingphysician, the uterine cavity will generally shift from theapproximately 30 degree angle of FIG. 3 to zero degrees which isgenerally considered the optimal position for embryo transfer to occur.In any event, it is preferred that no curve or significant angle existsbetween the cervix and uterine cavity.

The following protocol may be followed for this aspect of the procedure.Again, it should be noted that the following protocol is an exampleonly, and is not intended to limit the current invention. Several of thesteps below reference FIG. 4 which represents a split screen on thesonography machine showing two dimensional and three/four dimensionalviews.

1) Start in two dimensional sonography and just adjust Focus and Size,and position of the Render box.

2) Once the catheter passes the Cervical Internal Os, switch to 3D/4D.

3) Raise the reference image to the top green line. Adjust if necessaryusing the Y axis key as shown in the left side of FIG. 4.

4) Simultaneously on the 4D side of the screen, the tip of the catheterwill be seen as a bright light.

5) As the catheter moves forward toward the uterine cavity it can befollowed on the 4D screen.

6) Advancing catheter is followed on the 4D screen. Slight adjustmentsmay be continually made using the Track ball and its controls.

7) Once the catheter tip is over the MIP point, embryo(s) may bereleased as shown in FIG. 4 (right side).

8) At the time of the release an air bubble may be released. It willappear on the 4D display as a bright flash indicating the release of theembryo(s).

9) The retraction of the empty catheter may be followed using the 4Dimages. The air bubble will be seen left behind over the MIP point.

In another preferred embodiment, the present invention provides anintegrated system for calculating and displaying the MIP point on theultrasound machine display. In this embodiment of the invention, theoperator is relieved of the task of locating the MIP point manually andthe system automatically generates the MIP point for the physician. Thesystem features a 3 or 4D ultrasound machine with a computer capable ofcalculating the intersection point of the lines extending from eachfallopian tube and integrating the information with that obtained byultrasonography of the thickness and/or perfusion of the endometriallining of the uterine cavity. In a preferred embodiment of the system,the ultrasound machine is both a 3D and a 4D machine. In more preferredembodiments of the system, the GE Voluson 730 is adapted to perform thedetermination of the MIP point and to display it for the physician inreal time, thus providing guidance for the implantation procedure.

Accordingly, the current invention provides systems capable ofdetermining the optimal point of implantation for an embryo, therebymaximizing pregnancy rates resulting from IVF. The current inventionalso provides performing physicians with techniques and procedures toaccurately release and implant embryos in the uterus at the locationwhere the chances of pregnancy are optimal. The scope of the currentinvention extends to the use of other suitable sonography machinesbesides the units described above. Similarly, other protocols suitablefor use with other machines are within the scope of the currentinvention.

REFERENCES

1. Kan A K, Abdalla H I, Gafar A H. Embryo transfer: ultrasound guidedversus clinical touch. Hum Reprod 1999; 14:1259-61

2. Coroleu B, Carreras O, Veiga A. Embryo transfer under ultrasoundguidance improves pregnancy rates after in-vitro fertilization. HumReprod 2000; 15: 616-20

-   3. Wood E G, Batzer F, Go K J, Gutman J, Corson S L. Ultrasound    guided soft catheter embryo transfer will improve pregnancy rates in    in-vitro fertilization. Hum Reprod 2000; 15: 616-20

4. Tang O S, N G EH, So W W. Ultrasound-guided embryo transfer: aprospective randomized controlled trial. Hum Reprod 2001; 11: 2310-5

-   5. Mansour R T, Aboulghar M A. Optimizing the embryo transfer    technique. Human Reproduction 2002; 17:1149-1153.-   6. Baba K, Isihara O, Hayashi N, Saitoh M, Taya J, Kinoshita K.    Where does the embryo implant after embryo transfer in humans.    Fertil Steril 2000; 73: 123-125-   7. Frankfurter D, Trimachi J, Silva C, Keefe D. Middle to lower    uterine segment embryo transfer improves implantation and pregnancy    rates compared with fundal embryo transfer. Fertil & Steril 2004;    81: 1273-1277-   8. Pope C, Cook E, Amy M, Novak A, Grow D. Influence of embryo    transfer depthon in vitro fertilization and embryo transfer    outcomes. Fertil & Steril 2004; 81: 51-58-   9. Franco Jr J G, Martins A M V C, Baruffi R L R, Mauri A L,    Petersen C G, Felipe V, Contart P, Pontes A, Oliveira J B A. Best    site for embryo transfer: the upper or lower half of endometrial    cavity? Hum Reprod 2004; 19: 1785-1790-   10. Adams E C, Hertig A T, Rock J. A description of 34 human ova    within the first 17 days of development. Am J Anat 1956; 98:    435-493.

EXAMPLES

The following examples are provided to better illustrate the claimedinvention and are not to be interpreted as limiting the scope of theinvention. To the extent that specific materials are mentioned, it ismerely for purposes of illustration and is not intended to limit theinvention. Although certain preferred embodiments of the currentinvention have been described herein, it will be apparent to thoseskilled in the art to which the invention pertains, that variations andmodifications of the described embodiments may be made without departingfrom the spirit and scope of invention.

Example 1

A retrospective, observational study was conducted to evaluate the useof 3 dimensional/4 dimensional ultrasound in conjunction with the MIPpoint to facilitate embryo transfer and improve pregnancy rate.

Materials and Methods

Patients: 1222 patients underwent 3D/4D-Ultrasound guided embryotransfers at the IVF clinic. Embryo transfers were performed in allpatients anywhere from two to six days after oocyte retrieval in thefollowing manner.

Once the bladder was determined to be adequately full, by usingabdominal 2D ultrasound initially, the 3D ultrasound mode was thenemployed revealing the uterine cavity, after which the MIP Point wasidentified. The physicians sterilized the perineum in the usual fashionusing culture media and inserted a speculum into the vagina. Once theMIP was identified by the 3D/4D ultrasound machine, the physicianinserted the transfer catheter that he or she deemed appropriate.

The catheter tip was visualized during the entire insertion procedureand once the internal os was passed, the 4D mode was employed. Thisallowed us to follow the catheter tip in real-time on towards thepredetermined MIP point. Once the tip of the catheter was over the MIPPoint, the embryos were released inside the cavity and an embryo flashwas visualized. (FIG. 6). The empty catheter was then gently withdrawn,and checked by the embryologist for remaining embryos. Once clearancewas received, the speculum was removed and the patient was kept in asupine position for 30 minutes before discharged home.

Example 2

Results

During all embryo transfer procedures, the uterine cavity was wellvisualized using 3D/4D ultrasonography and the MIP point was wellidentified. During the time period evaluated, a total 1222 patientsunderwent 3D/4D ultrasound guidance utilizing the MIP point. Theiraverage age was 37.6 years and the pregnancy rate was 36.66%. A total of16 different physicians performed the transfers, with two of thesephysicians together performing 65% of the transfers. The ultrasound wasperformed by the same individual in all cases. Physicians reportedimproved visualization and were accepting to the incorporation of the3D/4D sonography in the embryo transfer.

While the IVF technology and success rates have come a long way, therestill remains room for improvement. The pregnancy rate is highlyinfluenced by the quality of the embryos, the receptivity of theendometrium and by the transfer technique (5).

There is still no consensus of what the ideal choice for implantation isfor embryos. In a study by Baba et al, embryos were transferred to themidfundal area in 60 patients. Among the 22 pregnancies, 80% of theembryos implanted in the areas to which they were transferred, while 20%implanted in other areas (6).

The location of embryo transfer in respect to the uterine anatomy alsovaries among physicians. Some studies have shown that the optimallocation for embryo transfer is 0.5-1 cm away from the uterine fundus(3), while some believe that the tip of the catheter should be 1.5 cmfrom the uterine fundus (2). However, others have shown that transfershould be in the lower to middle uterine segment (7). In a differentstudy by Pope et al, it was demonstrated that for every additionalmillimeter the embryos are placed away from the uterine fundus, theclinical pregnancy rate increases by 11% (8). In a recent randomizedstudy by Franco et al, embryos were deposited in the lower or upper halfof the endometrial cavity and there was no difference in pregnancy orimplantation rates (9).

From early work on surgically removed uteri of Adams et al, implantationwas found to take place in the upper half of the uterine cavity, most onthe posterior wall of the uterus (10). This further supports the MIPPoint as an advantageous spot, mimicking implantation in the generalpopulation. Since 3D/4D ultrasonography allows us to identify the MIPpoint with great ease, it is now possible to use the combination of MIPand 3D/4D sonography to accomplish embryo transfers accurately. Thus,the Maximal Implantation Potential Point can be readily identified andindividualized for each patient. Embryo transfers at the MIP wereassociated with good implantation and pregnancy rates.

1. A method of increasing pregnancy rates during in vitro fertilization,comprising determining the MIP point and guiding an implant catheter tosaid MIP point.
 2. The method of claim 1, wherein said MIP point is theintersection of two lines extending from the fallopian tubes in theuterine cavity.
 3. The method of claim 2, wherein said MIP point islocated where the endometrial lining is the thickest.
 4. The method ofclaim 1, wherein an ultrasound machine is used to determine said MIPpoint and to guide the implant catheter.
 5. The method of claim 1,wherein said MIP point is determined by an integrated system.
 6. Themethod of claim 5, wherein said integrated system comprises anultrasound machine.
 7. The method of claim 5, wherein said integratedsystem comprises a 4D ultrasound machine.
 8. The method of claim 5,wherein said integrated system comprises a 3D ultrasound machine.
 9. Themethod of claim 5, wherein said integrated system comprises a GeneralElectric Voluson 730 sonography machine.
 10. The method of claim 5,wherein said integrated system determines and displays the MIP point bycalculating the intersection of the lines extending from the fallopiantubes and identifying the area of thickest endometrial lining.
 11. Themethod of claim 1, further comprising (a) expanding the bladder anappropriate amount to shift the uterus from an anteflexed position tolessen the angle between the cervix and the uterine cavity, (b) locatingthe MIP point using three dimensional sonography and (c) implanting theembryo in the uterus with the aid of four dimensional sonography. 12.The method of claim 11, wherein said angle may be viewed using twodimensional sonography.
 13. The method of claim 11, wherein said angleis approximately 30 degrees.
 14. An integrated system for calculatingand displaying the MIP point comprising an ultrasound machine.
 15. Thesystem of claim 14, wherein said ultrasound machine is a 4D ultrasoundmachine.
 16. The system of claim 14, wherein said ultrasound machine isa 3D ultrasound machine.
 17. The system of claim 14, wherein saidultrasound machine is a General Electric Voluson 730 sonography machine.18. The system of claim 14, wherein said system determines and displaysthe MIP point by calculating the intersection of the lines extendingfrom the fallopian tubes and identifying the area of thickestendometrial lining.